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• W2912602247 abstract "Abstract APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in colorectal cancer. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apcmin mice has raised questions about the effects of PPARD on aberrant β-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (ApcΔ580) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed β-catenin activation via up- or downregulation of BMP7/TAK1 signaling and strongly promoted or suppressed colorectal cancer, respectively. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewal. Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in ApcΔ580 mice, whereas treatment with PPARD antagonist GSK3787 suppressed tumorigenesis. PPARD expression was significantly higher in human colorectal cancer–invasive fronts versus their paired tumor centers and adenomas. Reverse-phase protein microarray and validation studies identified PPARD-mediated upregulation of other proinvasive pathways: connexin 43, PDGFRβ, AKT1, EIF4G1, and CDK1. Our data demonstrate that PPARD strongly potentiates multiple tumorigenic pathways to promote colorectal cancer progression and invasiveness. Significance: These findings address long-standing, important, and unresolved questions related to the potential role of PPARD in APC mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances APC mutation-dependent tumorigenesis." @default.
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• W2912602247 date "2019-03-01" @default.
• W2912602247 modified "2023-10-18" @default.
• W2912602247 title "Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion" @default.
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• W2912602247 doi "https://doi.org/10.1158/0008-5472.can-18-1790" @default.
• W2912602247 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6397663" @default.
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